This Application is a 371 of PCT/GB98/03169 filed Oct. 22, 1998.
The present invention relates to coumarin derivatives, particularly hymecromone, to pharmaceutical compositions containing them and to their use in the treatment of disorders of the liver, kidney, pancreas, bladder and gastro-intestinal tract.
The liver is a complex organ with many diverse functions. It is the central organ of metabolism of carbohydrates, proteins, and fat. It stores glycogen and takes part in regulating blood sugar, and stores other essential substances such as vitamins and factors concerned in haemopoiesis. It synthesises fibrinogen, prothrombin, heparin, and plasma proteins, and is a site of destruction of deteriorated red blood cells. It is also the chief detoxicating organ of the body rendering unwanted substances innocuous.
Viral hepatitis refers to infection of the liver caused by a group of hepatitis viruses. Those so far identified are designated A, B, C, D and E. Other viruses such as Epstein-Barr virus and yellow fever virus may be secondary causes of hepatitis and nonviral infections, drugs, chemicals and alcoholism may also cause hepatitis. One of the main treatments for the various viral hepatitis infections is alpha or beta interferon, but in many cases it is not particularly effective. Other drugs that may produce a therapeutic response include lamivudine, ursodeoxycholic acid and vidarabine.
Primary biliary cirrhosis is a chronic liver disease of unknown aetiology, which develops due to progressive destruction of small and intermediate bile ducts within the liver, subsequently evolving to fibrosis and cirrhosis. Over 90% of patients are female, usually aged between 40 and 60 years. The disease is thought to be autoimmune in nature, perhaps triggered by a micro-organism in the environment and most patients exhibit autoantibodies to mitochondria. The disease is slowly progressive but no specific treatment is available.
Wilson""s disease is due to an inborn error of liver metabolism leading to the accumulation of toxic concentrations of copper. Gilbert""s syndrome is an inherited disorder that affects the way bilirubin is handled by the liver. Symptoms include mild jaundice, fatigue and abdominal pain. Again in both Wilson""s disease and Gilbert""s syndrome, there is no real effective treatment.
Accordingly there is a constant need for new compounds to treat the various liver disorders.
The inventor has now found that certain organic compounds (including naturally occurring extracts are effective in the treatment of various liver and other disorders.
Accordingly in a first aspect of the invention there is provided use of a compound of the Formula 2: 
wherein:
W is H or a xcex2-D-glucopyranosyloxy group,
X is OH, and
Y and Z are independently H, C1-6 alkyl, or C1-6 alkoxy and pharmacologically acceptable derivatives thereof in the manufacture of a medicament for the treatment or prophylaxis of a disease selected from liver, kidney, pancreatic, bladder, and gastro-intestinal disorders and disorders treatable by reducing the concentration or activity of transaminase enzymes, said disease not being treatable with a choleretic or biliary antispasmodic agent.
Preferably Z is methyl.
Examples of known compounds covered by Formula 2 are. as follows: fraxin (7,8-dihydroxy-6-methoxycoumarin-8-xcex2-D-glucoside), umbelliferone (7-hydroxycoumarin), skimmin (7-(glucosyloxy)coumarin), and hymecromone (7-hydroxy-4-methylcoumarin).
All compounds of Formula 2 are hereinafter referred to as xe2x80x9ccompounds of the inventionxe2x80x9d.
The compound that the inventor has done most work on and which has been found to be particularly effective is hymecromone (CAS Registry no. 90-33-5).
Although hymecromone is primarily used for the fluorometric determination of enzyme activity (Clin. Chim. Acta., 39,49 (1972); Anal. Biochem., 54,40 (1973)) it is also known as a choleretic (agent which aids the excretion of bile) and a biliary antispasmodic, and has been administered in doses of 300 mg-400 mg. (The Merck Index, 12th Edition, 4903 and Martindale, The Extra Pharmacopoeia, 31st Edition p1715). A more soluble form of hymecromone is disclosed in EP-A-0240874, and tablets of hymecromone for improving the excretion of bile are known from U.S. Pat. No. 3,175,943. The choleretic and biliary antispasmodic activity of hymecromone also is referred to in Petrioli (Fortschr. Med. 1979 Jul. 5; 97 (25-26):1174-8) and U.S. Pat. No. 4,241,047.
Hymecromone is commercially available from ABCR GmbH and Co Kg (Karlsruhe, Germany, Acros organics (Geel, Belgium), Loba Feinchemie AG (Fischamend, Austria), Sigma-Aldrich Fine Chemicals (Poole, Dorset, UK). Hymecromone is also available as a natural occurring extract of Manna Ash known as Fraxin.
By pharmacologically acceptable derivatives of the compounds of Formula 2, it is meant to include prodrugs, salts, solvates, esters, ethers, amides, glycosylated derivatives, and including methylated, aminated and acetylated derivatives.
By prodrug is meant any compound, which is capable of being metabolised in vivo to give a compound of Formula 1.
By salt it is meant to include pharmaceutically acceptable salts derived from an appropriate base such as alkali metal salts (e.g. sodium or potassium), alkaline earth metals (e.g. magnesium or calcium), ammonium and NX4(wherein X is C1-4 alkyl), or salzs of a hydrogen atom including salts formed from organic and inorganic acids such as those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, oxalic, fumaric, maleic, xaloacetic, methanesulphonic, ethanesulphonic, xcfx81-toluenesulphonic, benzenesulphonic and isethionic acids.
The compounds of the invention, particularly hymecromone, have hepatoprotective and/or hepatoregenerative properties. Liver disorders which can be treated comprise hepatitis including infective hepatitis (e.g. viral hepatitis of types A, B, C, D and E), chronic active hepatitis, acute infective hepatitis, toxic hepatitis (e.g. as caused by drugs and narcotics X-rays, solvents, chemotherapy, and alcohol abuse), steatosis hepatitis, acute parenchymatous hepatitis, amoebic hepatitis, cytomegalic hepatitis, enzootic hepatitis, familial hepatitis, homologous serum hepatitis, intestitial hepatitis, suppurative hepatitis, and trophopathic hepatitis. Various cirrhosis of the liver conditions which can be treated include primary and secondary biliary cirrhosis, alcoholic cirrhosis, annular cirrhosis, atrophic cirrhosis, bacterial cirrhosis, capsular cirrhosis, cardiac cirrhosis, fatty cirrhosis lymphatic cirrhosis and pigmentary cirrhosis. Yet further liver disorders against which the compounds of the invention are effective are Wilson""s disease and Gilbert""s svndrome.
The compounds of the invention are particularly effective in protecting the liver from the toxic effects of anabolic steroids, alcohol, chemotherapy, solvents, drugs, and environmental pollution.
Early investigations also suggest that compounds of the invention such as hymecromone will also be effective in the treatment or prophylaxis of disorders of the kidney (e.g. cirrhosis of the kidney), pancreas (e.g. pancreatitis), bladder and castrointestinal tract (e.g. cirrhosis of the stomach).
The invention can also be used to rejuvenate healthy people, especially those ex posed to heavy physical labour, the elderly a nd otherwis e healthy people recovering from illness, and sportsmen (especially those using anabolic steroids).
Without being bound by theory, it is thought that the corpounds of the invention are at least partly effective by reducing the concentration or activity in the peripheral blo od of transaminase enzymes, such as serum glutamic oxaloacetic transaminase (SGOT) or aspartate aminotransferase (AST), serum glutamic pyruvic transaminase (SGPT) or alanine transaminase (ALT), and gamma glutamyl traospe)tidase (GGT).
The invention also provides a composition comprising a compound of Formula 2 in combination with one or more of bee pollen, matricaria camomile, asperula oderata, royal jelly or honey.
The compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain for example 50 mg to 2000 mg preferably 20 mg to 500 mg depending on the condition being treated, the route of administration and the age, weight and condition of the patient. In the case of a compound of the invention suspenuhed in hney, a unit dosage would be relative to on e or more spoonfuls of the honey. The patient should preferably receive in the region of rug to 50 g per month, advantageously about 25 g to 28 g/month of a compound of the invention. Each unit dose may be administered once, twice, three or more times daily.
The compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
The compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
The compositions adapted forrectal administration may be presented as suppositories or enemas, and those adapted for vacinal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
The compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blocd cf the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition reau crind only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
Preferred unit dosage formulations are those containing a daily dose or sub-dose, as hereinabove recited, or an appropriate fraction thereof, of an active ingredient.
In a preferred oral composition, a compound of the invention is present together with one or more of the following other components preferably at the given relative quantities:
The composition can be suspended in honey and presented as a rejuvenating dietary supplement.
In a particularly preferred oral composition, there is provided a capsule containing from 100 to 300 mg (preferably about 210 mg) of a compound of the invention (e.g. hymecromone), from 3 to 7 mg (preferably about 5 mg) of camomile, and from 3 to 7 mg (preferably about 5 mg) of bee pollen.
The preferred source of a Compound of the invention (hymecromone) is Loba Feinchemie AG (Fischamend, Austria);